“De-escalation therapy” is a term that has become popular and suggests the need to reduce the spectrum or the number of antibiotics formerly prescribed for critical patients, upon clinical improvement and/or microorganism recovery. In fact, the major goal behind this concept is the use of broad-spectrum antibiotic agents as agents of choice for severe patients, instead of “reserving” the most potent agents after an inadequate clinical response or after the microorganism was recovered. Despite possible commercial concerns and an unproven but possible relationship with enhancing global antibiotic use, the concept was correct and in accordance with scientific evidence. However, the “de-escalation” component of the concept is very seldom reported, and no large clinical trial is available until today.
The evidences guiding this concept were clearly demonstrated in ventilator-associated pneumonia (VAP) conducted during the late 1990s and early 2000s, where an initial inadequate antibiotic coverage was associated with higher mortality rates using multivariate analysis (1–4). One review showed that, combining several similar studies, a statistically significant association between reduced mortality rate and an adequate initial antibiotic scheme were demonstrated (1). A few studies suggested that even antibiotic modification upon the availability of cultures did not alter the patient prognosis (3).
In fungal infections, some studies have demonstrated that the timing of antifungal prescription could alter mortality rates, with more timely treatments reducing mortality rates (5). In addition, a recent study showed that a correct initial antifungal class improved survival in patients with candidemia (6).
Finally, some studies have “proved the concept” for bloodstream infections, again correlating survival benefits with timely and adequate empiric antibiotic therapy (7, 8).
All the scientific data generated a change in antibiotic prescription all around the world, and this practice, along with other measures such as prompt volume restitution, corticosteroid, and optimal intensive care unit management, has significantly reduced mortality rates associated to septic shock (9).
To counterbalance the undesirable effect (at least for those concerned with it) of excess antibiotic consumption and antibiotic resistance, later strategies fortunately have focused on hospital-acquired infection control, some with considerable reductions in both catheter-related bloodstream infections and VAP (10).
On the other hand, some new problems have arisen in the subsequent years that need to be better understood, such as to renew the concept of broad and effective antibiotic therapy. Almost all of them are related to antibiotic resistance all around the world.
The first and presently most relevant issue for antibiotic therapy is the emergence of pan-resistant or at least multiresistant gram-negative bacteria. The emergence of Klebsiella species strains producing wide-spectrum β-lactamases (KPC) first reported in a New York City outbreak has become a global concern, with several other reports published thereafter (11, 12). A new β-lactamase originally described in New Delhi has rapidly spread and, although did not yet become a global threat, left few therapeutic options for serious infections caused by strains expressing this β-lactamase (13). Finally, pan-resistant or at least carbapenem-resistant strains of Pseudomonas species and Acinetobacter species have emerged and are presently part of the normal hospital flora in several parts of the world. For example, in a recent nationwide study in Brazil, around 50% of all isolates of these two species recovered from the blood of patients with bacteremia were resistant to meropenem/imipenem (14). As a commercial strategy, the “De-escalation” project has certainly granted significant short-term results for the sponsors, but as a lasting strategy it was a complete failure, because the carbapenems are now in many hospitals the target for de-escalation rather than the option for first and “infallible” initial therapy. The consequence of the emergence of the pan-resistant strains is the reemergence of the polymyxins as part of the antimicrobial armamentarium. Although these drugs are considerably more toxic with complete pharmaceutical properties not completely known, they can and must be now included in the treatment guidelines as the first initial treatment for serious infections in critically ill patients, at least in countries with high carbapenem resistance rates. If the polymyxins will become the target of global resistance, this is probably a matter of time, because resistance has already been reported (15).
Second, for gram-positive pathogens, although resistance rates for hospital-recovered agents are stable but in high percentages (mainly for Staphylococcus aureus and Enterococcus species) (14), the debate over vancomycin failures is still open. Vancomycin susceptibility cutoff values were reduced from 4 µg/mL to 2 µg/mL by the Clinical and Laboratory Standards Institute because of several reports of vancomycin failure (16). This effect in part is due to the presence of heteroresistant subcolonies of S. aureus with reduced susceptibility to vancomycin. The frequency of such colonies has a direct relation with vancomycin MICs (minimal inhibition concentrations) (16). Although the matter still remains debatable, some evidences today make it feasible to consider other drugs as the choice at least for bloodstream infections or other infections with MICs of 2 µg/mL or greater. At least one randomized study could show that telavancin was superior to vancomycin for a subgroup of strains with vancomycin MIC of greater than 1 µg/mL (17).
Third and last, global resistance rates to fluconazole are emerging around the world, with the predominance of non-albicans strains over Candida albicans as causes of serious fungal infections. Moreover, amphotericin toxicity has become a great concern, whereas new (but more expensive) drugs seem more reliable and even superior to fluconazole using a combined improvement index. For this reason, some Society Guidelines now postulate equinocandins or lipid formulations of amphotericin as first-line agents for suspected candidemia in critically ill patients (18).
Finally, what happened to antibiotic de-escalation? Unfortunately, much less effort has been used to prove the concept that spectrum reduction or limitation is safe. In fact, in a recent meta-analysis, the concept could not even be considered because not a single randomized study had taken place during the period considered (19).
On the other hand, evidence absence is not the same as evidence of absence. Small controlled studies and a considerable number of observational data have shown that the concept can be safe, can reduce antibiotic related adverse effects, and can even reduce susceptibility rates and reinfection episodes (20–25). Three points may, however, be the cornerstone of a safe protocol for antibiotic de-escalation: first, de-escalation can take place only when patients’ clinical status shows relevant clinical improvement, or infection is ruled out (this may be true mainly for pneumonia, because the specificity of clinical markers is not as accurate). Second, cultures must be collected and, when clinically relevant, such as blood isolates, should guide antibiotic change when regarded safe. Third, recognize that there are several modalities that can accomplish antibiotic optimization goals: change antibiotic to narrower spectrum (for patients with less severe condition and when toxicity is a concern, such as in patients who receive polymyxins or aminoglycosides as empirical therapy), reduce the number of antibiotics prescribed (the most illustrative example is with suspected bloodstream infections, when both gram-positive and gram-negative and sometimes Candida species are an initial consideration, but only one agent is later disclosed), and shorten antibiotic treatments (for instance, in VAP in nonimmunocompromised host without Pseudomonas and Acinetobacter as agents). All these can be tried, and the general practice believes that these strategies are safe. On the other hand, to definitely put in practice the “de-escalation concept,” comparative large trials must be designed and sponsored to put this practice at the same level of evidence of wide initial empiric antibiotic treatments.
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